In this Phase I proposal, the use of a novel dry powder coating technique applied to inhaled formulations for improved macrophage-targeting and sustained release of tuberculosis drugs will be investigated. Previously, polymeric microspheres were shown to be effective in targeting TB-infected macrophages and as localized delivery systems in TB-infected guinea pigs. However, low encapsulation efficiency ( less than 5 percent) and high polymer load due to long degradation rate (greater than 1 week) limited their use in inhalation therapy. Nanosphere, Inc. proposes to apply a polymeric coating on dry powders using a recently developed Pulsed Laser Deposition (PLD) coating technique. This method has been shown to form nanometer-thick continuous coatings that sustain the release rate on a variety of materials for several hours under low vacuum. While this technique has many applications in the pharmaceutical industry, nanometer-thick coatings are of particular interest in localized pulmonary drug delivery where only a narrow range of particle sizes is applicable (1 to 5 microns). Hence, the aim of this proposal is to assess the processing parameters involved in this PLD technique to enhance the incorporation of two model drugs (isoniazid and rifampin) into polymeric coated particles and test the dissolution rate, cell toxicity and activity in cell culture with Mycobacterium tuberculosis infected alveolar macrophages. PROPOSED COMMERCIAL APPLICATION: While the proposed research is specifically of interest in improving inhaled dry-powder formulations for localized release in the lungs, other applications for these relatively new delivery systems potentially include oral, pulmonary, transdermal, ocular, and injectable formulations.